This study was conducted at two clinical centers. The succeeding data presented cover all of the patients who participated in the study at both centers.
Nineteen men, aged 65 to 75 years, and 12 women, from 58 to 70 years old, who had PVCs at an hourly rate of at least 30 were admitted. Eighteen of the 31 patients were diagnosed as having arteriosclerotic heart disease, while in eight patients the tachyarrhythmia was related to valvular heart disease, three had idiopathic ventricular arrhythmia, and two had cardiomyopathy. Six patients had a history of myocardial infarction, and eight had undergone coronary bypass surgery. In two thirds of the patients, PVCs occurred at hourly rates between 60 and 719.
Excluded from the study were patients who had had a myocardial infarction within the preceding two weeks, patients with sinus bradycardia, second- or third-degree AV block, patients with supraventricular arrhythmias, and patients using concomitantly other antiarrhythmic agents or any investigational drugs. Also excluded were pregnant women, hypertensive individuals and patients with epileptic disorders. At the time of study initiation, the patients had been suffering from their arrhythmias for periods ranging from about one month to 17 years.
The patients were screened by history and a physical examination including a 12-lead ECG. In addition, two 24-h Holter recordings were made—usually on consecutive days—to establish the baseline (untreated) rate of PVCs. Patients who had previously been receiving antiarrhythmic medication including mexiletine were to discontinue such treatment for at least two days before Holter electrocardiography was instituted. Patients previously treated with mexiletine were eligible for admission to the study only if they had a history of satisfactory response to administration of the drug at an 8-h dose interval. Admission laboratory tests, repeated at the end of the study, included a complete blood cell count, blood chemistry studies and a urinalysis.
All patients gave their written consent to participation in the study on a form approved by an institutional review board.
Patients not previously treated with mexiletine were given a loading dose of 400 mg of mexiletine followed at 8-h intervals by doses of 200 mg. The capsules were always taken with food. To determine the response to this regimen, a Holter ECG recording was made during a 24-h period at any time between one and seven days after the first day of 8-h treatment.
If the average hourly PVC rate was not reduced by at least 50 percent of the average rate shown on the two baseline recordings, the dose given every 8 h was increased by 100 mg to 300 mg every 8 h, and another Holter recording was obtained within the same period as just mentioned. If the monitor tape again failed to show this degree of suppression of ectopic activity, the dose could be increased by the same amount to 400 mg every 8 h and the monitoring procedure repeated. If, on the other hand, arrhythmia control was not satisfactory at the highest allowable dose of 400 mg every 8 h, the patient was withdrawn from the study.
If within a week after Holter monitoring results had shown that the patients arrhythmia was reduced by at least 50 percent on the 8-h dosing schedule, another 24-h ambulatory ECG recording was obtained to confirm adequate control. This required that the hourly rate of extrasystoles did not exceed by more than 15 percent the average rate recorded on the previous Holter monitoring. If the previous measure of control was not being maintained and the patient had not reached the maximum dose level, upward dose titration was initiated as previously noted and the response was monitored by new Holter recordings.
Patients who had previously been treated with mexiletine every 8 h interrupted therapy for two days and were then given a 400-mg loading dose of the drug. Thereafter, they returned to the dose level that had proved safe and effective prior to the study. If they then failed to reach the goal reduction of the PVC rate, the dose was raised and the response was monitored as described previously.
After Holter confirmation of continuing satisfactory arrhythmia control with 8-h dosing, the 12-h regimen was substituted, using a dose of300 mg twice a day. If the Holter recording made after 48 h on this dose showed that the number of PVCs was greater than that seen on the 8-h schedule, the dose was titrated in daily increments of 100 mg (daily doses of 700, 800 or 900 mg) until the number of PVCs was equal to or below that during the 8-h regimen.
Once the target reduction of the hourly PVC rate was reached, the patient continued to be treated with the same dose, and a week later another 24-h Holter recording was made to confirm persistence of this response. If on this last Holter recording the hourly rate of PVCs did not exceed by more than 15 percent the final PVC rate while the patient was receiving 8-h therapy, no further upward dose titration was done. In the absence of this measure of control at the maximum dose level, titration was continued and the response was monitored as before.
In addition to PVCs, hourly rates of couplets and of episodes of ventricular tachycardia (defined as runs of three or more consecutive PVCs) were recorded at baseline and at the end of titration on the 8- and 12-h regimens.